Regulated IRE1-dependent mRNA decay sets the threshold for dendritic cell survival

Area of Science:

• Immunology
• Cell Biology
• Molecular Biology

Background:

• The IRE1-XBP1 signaling pathway is crucial for cellular defense against endoplasmic reticulum (ER) stress and immune cell development.
• Conventional type 1 dendritic cells (cDC1s) rely on this pathway for survival and function.

Purpose of the Study:

• To investigate the tissue-specific role of XBP1 in mucosal cDC1 survival under ER stress.
• To elucidate the adaptive mechanisms employed by intestinal cDC1s to overcome ER stress-induced cell death.

Main Methods:

• Utilized genetic models to ablate XBP1 in splenic and mucosal cDC1s.
• Assessed cell survival, ER stress markers (CHOP, JNK), protein synthesis, and mRNA decay.
• Investigated the impact of combined IRE1 endonuclease and XBP1 loss.

Main Results:

• Loss of XBP1 in splenic cDC1s caused functional changes but not cell death.
• Mucosal cDC1s exhibited tissue-specific survival differences: lung cDC1s died, while intestinal cDC1s survived.
• Intestinal cDC1 survival was linked to suppressed protein synthesis via integrated stress response and enhanced regulated IRE1-dependent mRNA decay (RIDD).
• Simultaneous loss of IRE1 endonuclease and XBP1 led to intestinal cDC1 death.

Conclusions:

• Mucosal dendritic cells employ distinct ATF4- and IRE1-dependent adaptive strategies to ensure survival during ER stress.
• Tissue microenvironment significantly influences the response of cDC1s to ER stress.
• RIDD and integrated stress response are key protective mechanisms for intestinal cDC1s.